Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi

Susanne Radke, Harish Chander, Patrick Schäfer, Gregor Meiss, Rejko Krüger, Jörg B. Schulz, Doris Germain*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

138 Citations (Scopus)

Abstract

We report here that blocking the activity of the 26 S proteasome results in drastic changes in the morphology of the mitochondria and accumulation of intermembrane space (IMS) proteins. Using endonuclease G (endoG) as a model IMS protein, we found that accumulation of wild-type but to a greater extent mutant endoG leads to changes in the morphology of the mitochondria similar to those observed following proteasomal inhibition. Further, we show that wildtype but to a greater extent mutant endoG is a substrate for ubiquitination, suggesting the presence of a protein quality control. Conversely, we also report that wild-type but not mutant endoG is a substrate for the mitochondrial protease Omi but only upon inhibition of the proteasome. These findings suggest that although elimination of mutant IMS proteins is strictly dependent on ubiquitination, elimination of excess or spontaneously misfolded wild-type IMS proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient. One implication of our finding is that in the context of attenuated proteasomal function, accumulation of IMS proteins would contribute to the collapse of the mitochondrial network such as that observed in neurodegenerative diseases. Another implication is that such collapse could be accelerated either by mutations in IMS proteins or by mutations in Omi itself.

Original languageEnglish
Pages (from-to)12681-12685
Number of pages5
JournalJournal of Biological Chemistry
Volume283
Issue number19
DOIs
Publication statusPublished - 9 May 2008
Externally publishedYes

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